title: Caffeine and other methylxanthines as interceptors of food-borne aromatic mutagens: inhibition of Trp-P-1 and Trp-P-2 mutagenic activity.
abstract: Caffeine is one of the most important biologically active food components. In this article, we demonstrate that caffeine and other methylxanthines significantly reduce the mutagenic activity of two food-derived heterocyclic aromatic amines, Trp-P-1 and Trp-P-2 in the Salmonella typhimurium TA98 strain. Moreover, protection against Trp-P-1-induced mutagenicity was independent of liver S9 enzymatic fraction, suggesting that mechanisms other than modulation of mutagen bioactivation can contribute to the observed protective effects. UV-vis spectroscopy and computational studies revealed that methylxanthines intercept Trp-P-1 and Trp-P-2 in noncovalent molecular complexes, with association constants (KAC) in the 10(2) M(-1) range. Enthalpy values (ΔH about -30 kJ·mol(-1)) of mutagen-methylxanthine heterocomplexation obtained microcalorimetrically correspond to stacking (π-π) interactions. Finally, we demonstrated that the biological activity of Trp-P-1 and Trp-P-2 is strictly dependent on the presence of the mutagen in a free (unbound with methylxanthine) form, suggesting that mutagen sequestration in stacking heterocomplexes with methylxanthines can decrease its bioavailability and diminish its biological effects.
authors.affiliation: Laboratory of Biophysics, Intercollegiate Faculty of Biotechnology UG-MUG , Kładki 24, 80-822 Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Woziwodzka
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Gołuński
authors.forename: Dariusz
authors.initials: D
authors.lastname: Wyrzykowski
authors.forename: Rajmund
authors.initials: R
authors.lastname: Kaźmierkiewicz
authors.forename: Jacek
authors.initials: J
authors.lastname: Piosik
mesh_terms: D000818:Animals; D002110:Caffeine / Q000737:chemistry / Q000494:pharmacology*; D002243:Carbolines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics; D014970:Xanthines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002243:Carbolines; D009153:Mutagens; D014970:Xanthines; C008514:methylxanthine; D002110:Caffeine; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole